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Marie E. Dorat, CQA, CAA
IPRF, LLC – RA/QA Consulting & International Product Registration
EU-FDA Joint Initiative
The U S Food and Drug Administration (FDA) and European Medicines Agency (EMA) Good Clinical Practice (GCP) initiative started a joint inspection program in September 2009. This inspection program targets investigator sites, sponsors, and contract research organizations (CROs) in either the US or the European Union (EU).
These joint GCP inspections come under anarrangement between the European Commission, the European Medicines Agency (EMA), and theFDA. The initiative allows them to streamline thesharing of information on inspection and observations and facilitates the conduct of collaborative inspections. The goal is for European Union (EU) inspectors and FDA inspectors to have the same information about a facility.
What Are They Looking For?
FDA Investigator site inspections are product specific, i.e., drugs, biologics or medical devices. The site investigators will follow FDA regulations specifically, including regulations found in 21 CFR 312 (Investigational New Drug Application) and 21 CFR 812 (Investigational Device Exemption). When inspections of sponsors, CROs, and monitors occur, FDA will compare the practices and procedures conducted by the sponsor or CRO against the commitments made in the FDA application.
This article is related to Whitepaper: Managing Change Control to Comply with FDA and EU Regulations. To get the full details, please download your free copy.
In the EU, oversight relies on the GCP Inspection Services Group of the EMA. EMA inspections are at the request of their division or it could be the result of special interest in a particular product or simply to verify compliance to GCP requirements. Their inspectors use the Joint program to ensure conformity among Member States and to make sure trials stay in accordance with recognized agreements among European countries. Requirements for the conduct of clinical trials in the EU, including GCP, good manufacturing practice (GMP) and inspections of these, have been implemented in the Clinical Trial Directive (Directive 2001/20/EC) and the GCP Directive (Directive 2005/28/EC) and related guidance documents.
Preparing for the Inspection
I highly recommend conducting a mock inspection to prepare the staff. Use the ICH/GCP consolidated guidance to develop a comprehensive checklist and specifically consider creating an Essential Documents checklist.
- Review all of the site documentation. Review GCP requirements, protocols with the staff
- Ensure all appropriate approvals have been obtained from the sponsor and/or IRB
- Verify the responsibilities on the Delegation Authority have been followed
- Focus on documentation accuracy and compliance
- Look for gaps, correct those that can be corrected provide clarification for items that cannot be corrected at this time – typically a Note to File
- Locate any missing records
- Resolve any unresolved or outstanding issues if possible
- Compare your source documents with the case report form (CRF) entries to ensure the data has been entered correctly
- Review your Regulatory binder to verify it contains current essential documents
- Review your Inform Consent forms and the procedure for obtaining informed consent
During this mock inspection, conduct practice interviews with your staff, determine who will provide information regarding which area. Let them practice answering questions. Discuss how they will answer questions from the inspector. Inform them they should:
- Be concise; answer only the question that is asked
- Answer honestly and openly
- DO NOT volunteer information
- DO NOT guess or speculate
- DO NOT argue
If your inspection was announced, be prepared for the inspection. Organize a triage:
- Reserve a private room for the inspectors
- Have available the medical records and case report forms for all subjects enrolled in the study
- Have essential documents binder ready
- Prior to their arrival set up computer access to appropriate files
- Have temporary password with limited access available
- Prepare a quick reference guide to your database
- Have a copy machine located nearby
During the Inspection
The FDA inspector begins an inspection by presenting credentials and the original signed FDA-482 form, Notice of Inspection, to the most responsible person at the firm that is being inspected, usually the management representative. In comparison, there is no formal documentation issued during the start of an inspection by the EU. Instead, everything is discussed verbally during an opening discussion held to discuss the purpose of the inspection, expectations and documents or people they will need to interview.
FDA nor EU inspectors are required to sign any company-requested documents. FDA inspectors are instructed not to sign any non-FDA forms, but they are required to report these requests in their written Establishment Inspection Report (EIR). The EMA is the same as the FDA in this regard.
Both the FDA and the EU inspectors will request a tour of the facility and ask questions to confirm and evaluate that resources, personnel, and the overall facility are appropriate for the trial being conducted. During the tour, they may request procedures and other documents, i.e., temperature controls/records for storage area where the product is maintained.
The EU inspectors maintain a tracking log of all documents requested and received. This document is given to the site being inspected to ensure that all requests are documented. In comparison, FDA only makes formal verbal requests for documents. Identify a staff member who will remain with the inspectors to take note of all requests, questions and comments. Also make sure all documents provided to the inspector are stamped ‘Confidential.’ Whenever possible, remove subject identifiers from the copies provided to the inspector.
The Closeout Meeting
Prior to departing the firm, the FDA inspectors are required to provide the inspection site an FDA-483, a List of Objectionable Conditions, in writing, if any significant objectionable observations relating to products and/ or processes or other violations of the FD&C Act and related Acts were found during the inspection. The FDA will only list observations which are significant and relative to regulated products or processes being inspected. If an observation was made during a prior inspection that has not been corrected or is recurring, it will be noted on the FDA-483.
The EU inspectors do not provide a written list of objectionable findings at the close of the inspection, but instead will discuss the observations verbally in the closeout meeting. The EMA provides an inspection report for each site inspected as well as an Integrated Inspection Report (IIR). The audit reports are issued in English. For site inspections, the investigator and the sponsor are copied on the report, whereas for CRO/sponsor inspections only the auditees are copied.
During the closing meeting, take notes on all comments by the inspectors and any commitments made to the inspectors. Inform them of any corrections made during the audit. Discuss any objections you have to their interpretation of their observations. Try to clarify any issues before the inspectors leave, if possible.
Remember, be clear, be honest, be prepared!
Marie E Dorat is CEO of IPRF, LLC , a Regulatory/Quality consulting firm which assists companies working to obtain/maintain compliance. IPRF, LLC provides a cost-effective system to reduce international product registration document legalization time from two months to 2-5 days, allowing companies to get their product on the market ahead of the competition. Ms. Dorat is a hands-on quality professional with 13 years in the medical device and biopharmaceutical/pharmaceutical industries. She has a high level of expertise in the regulatory arena with an astute knowledge of quality systems. She also has extensive experience in validation, gap analysis, CAPA, change control, audits and training. She’s developed, implemented and executed clients’ quality management systems/e-QMS, ensuring compliance with cGxPs guidelines, ISO standards, and international regulations. Ms. Dorat is also a SME for the 360Predict e-QMS system and assisted in its development.
Contact Info: IPRF, LLC